The ever-increasing demand for chiral compounds and the impressive prevalence of fluorinated pharmaceuticals on the US drug market generate compelling motivation for the development of synthetic methods that yield practical access to multifunctional organofluorines. The introduction of strategies that provide control over the unique stability and reactivity patterns of fluorinated species offers invaluable opportunities to streamline chemical synthesis of current and future drugs. The versatile chemistry of terminal ynamides which have been barely investigated to date and new C- F functionalization methodology recently discovered in our lab bear similar promise. The goals of the proposed research are to introduce asymmetric methods for catalytic carbon-carbon bond formation with fluorinated nucleophiles generated either by mild deacylative C-C cleavage of readily available precursors or from multifunctional prenucleophiles, to continue our spearheading efforts with asymmetric ynamide addition reactions, and to develop new C-F functionalization chemistry. The general feasibility of the planned activities and the synthetic utility prospects are highlighted with ample proof- of-concept results and mechanistic insights. Considerable emphasis will be placed on the introduction of currently elusive reactions and new methodologies, for example unprecedented asymmetric Michael addition/Nef reactions, C-F activation for selective carbon-carbon and carbon-heteroatom bond formation, and base-free ynamide additions. In addition, the overall usefulness of the proposed multifunctional chiral building blocks for the total synthesis of biologically active compounds will be explored. The reaction development efforts will be guided by detailed mechanistic studies and include screening and systematic optimization of a variety of organocatalysts and chiral ligands, including bisoxazolidines which have been developed previously in our laboratory. Altogether, the anticipated outcomes of this proposal are likely to afford new tools and directions for asymmetric catalysis with organofluorines and terminal ynamides as well as general reaction insights and synthetic opportunities that will be of interest to a wide range of synthetic and medicinal chemists.